! SUMMARY?PROJECT 1: PET MEASURES OF TAU AND AMYLOID PATHOLOGY. We propose in Project 1 to evaluate Tau PET measures in the entire Harvard Aging Brain Study (HABS) cohort, focusing on testing whether the PET measures of Tau and A? are related to each other and to measures of brain structure and function. This research will facilitate the intense efforts currently underway to develop disease-modifying treatments of Alzheimer's disease (AD), aided by biomarkers of these hallmark lesions that could potentially aid in diagnosis, disease staging, drug development, and treatment monitoring. In the proposed competing continuation, HABS participants will undergo PiB and T807 PET (estimated N=250; acquired in Core C: Imaging Core), with a representative subset (N=100) undergoing longitudinal T807 and FDG PET, in order to achieve the following aims: Aim 1: To characterize T807 PET in the HABS cohort in order to determine the anatomy of specific binding, relate binding to age, gender and APOE genotype, and identify suitable standard proxy measures of global burden and/or its stages of longitudinal change. Aim 2: To assess the interrelationships of Tau and A? deposition and their differential impact on regional connectivity, synaptic integrity, brain volume, and CSF markers. Aim 3: To evaluate the longitudinal change in Tau accumulation in relation to A?, connectivity, synaptic integrity, atrophy, and CSF markers, as well as to longitudinal cognition, coordinating with Project 4. !